{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTPBG, also known as 5T4, is an oncofetal cell surface glycoprotein that is aberrantly expressed in various cancers. Its tumor‐selective expression has allowed it to be exploited as a target for immunotherapy, where antibody–drug conjugates and therapeutic vaccines (e.g., TroVax) have been developed to not only harness immune recognition by CTLs but also to eliminate cancer stem cells and reduce locoregional recurrence in head and neck and colorectal cancers. TPBG’s immunogenic properties have been further supported by studies demonstrating the generation of specific CD8 T‐cell responses against 5T4 epitopes in patients, reinforcing its potential both as a biomarker and as a therapeutic target in diverse solid tumors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the mechanistic level, TPBG plays multiple roles in regulating key signaling pathways that govern cell movement, differentiation, and metastasis. Structural studies have revealed that specific leucine‐rich repeat regions of 5T4 are essential for its ability to inhibit canonical Wnt/β‐catenin signaling, thereby favoring alternative non‐canonical pathways that are associated with epithelial–mesenchymal transition and directional cell migration. In parallel, TPBG modulates chemotactic responses by facilitating functional CXCR4 expression while suppressing CXCR7‐mediated responses, as observed in models where TPBG’s regulation of the CXCL12 axis underpins cell migration and angiogenesis. These molecular functions underscore TPBG’s dual role as both a regulator of intracellular signaling and a mediator of the tumor microenvironment."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in cancer, TPBG is dynamically expressed during normal development and in specialized physiological contexts. In human embryonic stem cells, transient TPBG expression marks the onset of differentiation coinciding with loss of pluripotency, while in placental tissues TPBG is developmentally regulated and may influence maternal–fetal interactions and pathological conditions such as preeclampsia. In the vascular compartment, TPBG is upregulated under hypoxic conditions in pericyte‐like cells, where it activates CXCL12/CXCR7/ERK signaling and promotes reparative angiogenesis. Detailed mapping of its extracellular glycosylation and epitope structure further informs the development of TPBG‐targeted therapies across different clinical settings."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Samuel A Kerk, Kelsey A Finkel, Alexander T Pearson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "5T4-Targeted Therapy Ablates Cancer Stem Cells and Prevents Recurrence of Head and Neck Squamous Cell Carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-16-1834"}], "href": "https://doi.org/10.1158/1078-0432.CCR-16-1834"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27780858"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27780858"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Eyad Elkord, Adam Dangoor, Noel L Drury, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An MVA-based vaccine targeting the oncofetal antigen 5T4 in patients undergoing surgical resection of colorectal cancer liver metastases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunother (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/CJI.0b013e3181876ab3"}], "href": "https://doi.org/10.1097/CJI.0b013e3181876ab3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18833005"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18833005"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "William H Shingler, Priscilla Chikoti, Susan M Kingsman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification and functional validation of MHC class I epitopes in the tumor-associated antigen 5T4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int Immunol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/intimm/dxn063"}], "href": "https://doi.org/10.1093/intimm/dxn063"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18567615"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18567615"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Lucy J C Smyth, Eyad Elkord, Taher E I Taher, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CD8 T-cell recognition of human 5T4 oncofetal antigen."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.22018"}], "href": "https://doi.org/10.1002/ijc.22018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16646078"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16646078"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Saly Al-Taei, Josephine Salimu, Jason F Lester, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression and potential targeting of the oncofoetal antigen 5T4 in malignant pleural mesothelioma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Lung Cancer (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.lungcan.2012.03.008"}], "href": "https://doi.org/10.1016/j.lungcan.2012.03.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22498111"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22498111"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Yuguang Zhao, Tomas Malinauskas, Karl Harlos, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural insights into the inhibition of Wnt signaling by cancer antigen 5T4/Wnt-activated inhibitory factor 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Structure (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.str.2014.01.009"}], "href": "https://doi.org/10.1016/j.str.2014.01.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24582434"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24582434"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Owen J McGinn, Georgi Marinov, Saladin Sawan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CXCL12 receptor preference, signal transduction, biological response and the expression of 5T4 oncofoetal glycoprotein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.109488"}], "href": "https://doi.org/10.1242/jcs.109488"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22956548"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22956548"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Peter L Stern, Julie Brazzatti, Saladin Sawan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Understanding and exploiting 5T4 oncofoetal glycoprotein expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Semin Cancer Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.semcancer.2014.07.004"}], "href": "https://doi.org/10.1016/j.semcancer.2014.07.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25066861"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25066861"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Ping He, Shuheng Jiang, Mingze Ma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Trophoblast glycoprotein promotes pancreatic ductal adenocarcinoma cell metastasis through Wnt/planar cell polarity signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Med Rep (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/mmr.2015.3412"}], "href": "https://doi.org/10.3892/mmr.2015.3412"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25738465"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25738465"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Hang Su, Shichang Yu, Fashi Sun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LINC00342 induces metastasis of lung adenocarcinoma by targeting miR-15b/TPBG."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Biochim Pol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18388/abp.2020_5697"}], "href": "https://doi.org/10.18388/abp.2020_5697"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35452205"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35452205"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Christopher M Ward, Angela M Eastham, Peter L Stern "}, {"type": "b", "children": [{"type": "t", "text": "Cell surface 5T4 antigen is transiently upregulated during early human embryonic stem cell differentiation: effect of 5T4 phenotype on neural lineage formation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2006.02.006"}], "href": "https://doi.org/10.1016/j.yexcr.2006.02.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16616918"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16616918"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "David M Shaw, Andrew M Woods, Kevin A Myers, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Glycosylation and epitope mapping of the 5T4 glycoprotein oncofoetal antigen."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/0264-6021:3630137"}], "href": "https://doi.org/10.1042/0264-6021:3630137"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11903056"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11903056"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "S M K Alam, S Jasti, S K Kshirsagar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Trophoblast Glycoprotein (TPGB/5T4) in Human Placenta: Expression, Regulation, and Presence in Extracellular Microvesicles and Exosomes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Reprod Sci (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/1933719117707053"}], "href": "https://doi.org/10.1177/1933719117707053"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28481180"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28481180"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Helen L Spencer, Eva Jover, William Cathery, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of TPBG (Trophoblast Glycoprotein) Antigen in Human Pericyte Migratory and Angiogenic Activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arterioscler Thromb Vasc Biol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/ATVBAHA.119.312665"}], "href": "https://doi.org/10.1161/ATVBAHA.119.312665"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31018661"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31018661"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Shiho Okazaki, Akihiko Sekizawa, Yuditiya Purwosunu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Placenta-derived, cellular messenger RNA expression in the maternal blood of preeclamptic women."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Obstet Gynecol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/01.AOG.0000286761.11436.67"}], "href": "https://doi.org/10.1097/01.AOG.0000286761.11436.67"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17978129"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17978129"}]}]}]}